Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 291 (5510): 1983-1987

Copyright © 2001 by the American Association for the Advancement of Science

Filopodial Calcium Transients Promote Substrate-Dependent Growth Cone Turning

Timothy M. Gomez,*dagger ddagger Estuardo Robles,ddagger Mu-ming Poo,§ Nicholas C. Spitzer

Filopodia that extend from neuronal growth cones sample the environment for extracellular guidance cues, but the signals they transmit to growth cones are unknown. Filopodia were observed generating localized transient elevations of intracellular calcium ([Ca2+]i) that propagate back to the growth cone and stimulate global Ca2+ elevations. The frequency of filopodial Ca2+ transients was substrate-dependent and may be due in part to influx of Ca2+ through channels activated by integrin receptors. These transients slowed neurite outgrowth by reducing filopodial motility and promoted turning when stimulated differentially within filopodia on one side of the growth cone. These rapid signals appear to serve both as autonomous regulators of filopodial movement and as frequency-coded signals integrated within the growth cone and could be a common signaling process for many motile cells.

Department of Biology and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093, USA.
*   To whom correspondence should be addressed. E-mail: tmgomez{at}

dagger    Present address: Department of Anatomy, University of Wisconsin Medical School, Madison, WI 53706, USA.

ddagger    These authors contributed equally to this work.

§   Present address: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

Cell biology in neuroscience: Cellular and molecular mechanisms underlying axon formation, growth, and branching.
T. L. Lewis Jr., J. Courchet, and F. Polleux (2013)
J. Cell Biol. 202, 837-848
   Abstract »    Full Text »    PDF »
Imaging and Manipulating Calcium Transients in Developing Xenopus Spinal Neurons.
N. C. Spitzer, L. N. Borodinsky, and C. M. Root (2013)
Cold Spring Harb Protoc 2013, pdb.prot066803
   Abstract »    Full Text »    PDF »
Mechanosensitive TRPC1 Channels Promote Calpain Proteolysis of Talin to Regulate Spinal Axon Outgrowth.
P. C. Kerstein, B. T. Jacques-Fricke, J. Rengifo, B. J. Mogen, J. C. Williams, P. A. Gottlieb, F. Sachs, and T. M. Gomez (2013)
J. Neurosci. 33, 273-285
   Abstract »    Full Text »    PDF »
Calcium Signaling in Neuronal Development.
S. S. Rosenberg and N. C. Spitzer (2011)
Cold Spring Harb Perspect Biol 3, a004259
   Abstract »    Full Text »    PDF »
Spatial and temporal second messenger codes for growth cone turning.
X. Nicol, K. P. Hong, and N. C. Spitzer (2011)
PNAS 108, 13776-13781
   Abstract »    Full Text »    PDF »
Neuronal Activity-Regulated Gene Transcription in Synapse Development and Cognitive Function.
A. E. West and M. E. Greenberg (2011)
Cold Spring Harb Perspect Biol 3, a005744
   Abstract »    Full Text »    PDF »
Serotonin stimulation of cAMP-dependent plasticity in Aplysia sensory neurons is mediated by calmodulin-sensitive adenylyl cyclase.
A. H. Lin, J. E. Cohen, Q. Wan, K. Niu, P. Shrestha, S. L. Bernstein, and T. W. Abrams (2010)
PNAS 107, 15607-15612
   Abstract »    Full Text »    PDF »
Rac1 Modulates Stimulus-evoked Ca2+ Release in Neuronal Growth Cones via Parallel Effects on Microtubule/Endoplasmic Reticulum Dynamics and Reactive Oxygen Species Production.
X.-F. Zhang and P. Forscher (2009)
Mol. Biol. Cell 20, 3700-3712
   Abstract »    Full Text »    PDF »
Molecular noise of capping protein binding induces macroscopic instability in filopodial dynamics.
P. I. Zhuravlev and G. A. Papoian (2009)
PNAS 106, 11570-11575
   Abstract »    Full Text »    PDF »
Spontaneous Calcium Spike Activity in Embryonic Spinal Neurons Is Regulated by Developmental Expression of the Na+, K+-ATPase {beta}3 Subunit.
L. W. Chang and N. C. Spitzer (2009)
J. Neurosci. 29, 7877-7885
   Abstract »    Full Text »    PDF »
The Nitric Oxide-cGMP Pathway Controls the Directional Polarity of Growth Cone Guidance via Modulating Cytosolic Ca2+ Signals.
T. Tojima, R. Itofusa, and H. Kamiguchi (2009)
J. Neurosci. 29, 7886-7897
   Abstract »    Full Text »    PDF »
L-Type Calcium Channels Govern Calcium Signaling in Migrating Newborn Neurons in the Postnatal Olfactory Bulb.
D. P. Darcy and J. S. Isaacson (2009)
J. Neurosci. 29, 2510-2518
   Abstract »    Full Text »    PDF »
Neurite Outgrowth and In Vivo Sensory Innervation Mediated by a CaV2.2-Laminin {beta}2 Stop Signal.
S. B. Sann, L. Xu, H. Nishimune, J. R. Sanes, and N. C. Spitzer (2008)
J. Neurosci. 28, 2366-2374
   Abstract »    Full Text »    PDF »
Differential Outgrowth of Axons and their Branches Is Regulated by Localized Calcium Transients.
B. I. Hutchins and K. Kalil (2008)
J. Neurosci. 28, 143-153
   Abstract »    Full Text »    PDF »
Neuronal calcium sensor-1 modulation of optimal calcium level for neurite outgrowth.
K. Hui, G.-H. Fei, B. J. Saab, J. Su, J. C. Roder, and Z.-P. Feng (2007)
Development 134, 4479-4489
   Abstract »    Full Text »    PDF »
Spatial targeting of type II protein kinase A to filopodia mediates the regulation of growth cone guidance by cAMP.
J. Han, L. Han, P. Tiwari, Z. Wen, and J. Q. Zheng (2007)
J. Cell Biol. 176, 101-111
   Abstract »    Full Text »    PDF »
The largest growth cones in the animal kingdom: an illustrated guide to the dynamics of Aplysia neuronal growth in cell culture.
P. Lovell and L. L. Moroz (2006)
Integr. Comp. Biol. 46, 847-870
   Abstract »    Full Text »    PDF »
Sema3a1 guides spinal motor axons in a cell- and stage-specific manner in zebrafish.
M. Sato-Maeda, H. Tawarayama, M. Obinata, J. Y. Kuwada, and W. Shoji (2006)
Development 133, 937-947
   Abstract »    Full Text »    PDF »
Rac1 and RhoA Promote Neurite Outgrowth through Formation and Stabilization of Growth Cone Point Contacts.
S. Woo and T. M. Gomez (2006)
J. Neurosci. 26, 1418-1428
   Abstract »    Full Text »    PDF »
Cell adhesion molecules regulate Ca2+-mediated steering of growth cones via cyclic AMP and ryanodine receptor type 3.
N. Ooashi, A. Futatsugi, F. Yoshihara, K. Mikoshiba, and H. Kamiguchi (2005)
J. Cell Biol. 170, 1159-1167
   Abstract »    Full Text »    PDF »
Src-Dependent Tyrosine Phosphorylation at the Tips of Growth Cone Filopodia Promotes Extension.
E. Robles, S. Woo, and T. M. Gomez (2005)
J. Neurosci. 25, 7669-7681
   Abstract »    Full Text »    PDF »
Netrin-1 Induces Axon Branching in Developing Cortical Neurons by Frequency-Dependent Calcium Signaling Pathways.
F. Tang and K. Kalil (2005)
J. Neurosci. 25, 6702-6715
   Abstract »    Full Text »    PDF »
Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells.
W. J. Moody and M. M. Bosma (2005)
Physiol Rev 85, 883-941
   Abstract »    Full Text »    PDF »
Ca2+-Dependent Regulation of Rho GTPases Triggers Turning of Nerve Growth Cones.
M. Jin, C.-b. Guan, Y.-a. Jiang, G. Chen, C.-t. Zhao, K. Cui, Y.-q. Song, C.-p. Wu, M.-m. Poo, and X.-b. Yuan (2005)
J. Neurosci. 25, 2338-2347
   Abstract »    Full Text »    PDF »
Cyclic changes in keratocyte speed and traction stress arise from Ca2+-dependent regulation of cell adhesiveness.
A. D. Doyle and J. Lee (2005)
J. Cell Sci. 118, 369-379
   Abstract »    Full Text »    PDF »
Modulation of plasma membrane calcium-ATPase activity by local calcium microdomains near CRAC channels in human T cells.
D. M. Bautista and R. S. Lewis (2004)
J. Physiol. 556, 805-817
   Abstract »    Full Text »    PDF »
Coincidence detection enhances appropriate wiring of the nervous system.
N. C. Spitzer (2004)
PNAS 101, 5311-5312
   Full Text »    PDF »
Calcium signaling in chemorepellant Slit2-dependent regulation of neuronal migration.
H.-t. Xu, X.-b. Yuan, C.-b. Guan, S. Duan, C.-p. Wu, and L. Feng (2004)
PNAS 101, 4296-4301
   Abstract »    Full Text »    PDF »
Gradients and Growth Cone Guidance of Grasshopper Neurons.
A. T. Legg and T. P. O'Connor (2003)
Journal of Histochemistry & Cytochemistry 51, 445-454
   Abstract »    Full Text »    PDF »
Overlapping Microarray Profiles of Dentate Gyrus Gene Expression during Development- and Epilepsy-Associated Neurogenesis and Axon Outgrowth.
R. C. Elliott, M. F. Miles, and D. H. Lowenstein (2003)
J. Neurosci. 23, 2218-2227
   Abstract »    Full Text »    PDF »
Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide.
C. Guirland, K. B. Buck, J. A. Gibney, E. DiCicco-Bloom, and J. Q. Zheng (2003)
J. Neurosci. 23, 2274-2283
   Abstract »    Full Text »    PDF »
Regulation of an inactivating potassium current (IA) by the extracellular matrix protein vitronectin in embryonic mouse hippocampal neurones.
D. V Vasilyev and M. E Barish (2003)
J. Physiol. 547, 859-871
   Abstract »    Full Text »    PDF »
Trafficking of TrkA-Green Fluorescent Protein Chimerae during Nerve Growth Factor-induced Differentiation.
J. Jullien, V. Guili, E. A. Derrington, J.-L. Darlix, L. F. Reichardt, and B. B. Rudkin (2003)
J. Biol. Chem. 278, 8706-8716
   Abstract »    Full Text »    PDF »
Spontaneous Calcium Transients in Developing Cortical Neurons Regulate Axon Outgrowth.
F. Tang, E. W. Dent, and K. Kalil (2003)
J. Neurosci. 23, 927-936
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of Axon Guidance.
B. J. Dickson (2002)
Science 298, 1959-1964
   Abstract »    Full Text »    PDF »
Three Functionally Distinct Adhesions in Filopodia: Shaft Adhesions Control Lamellar Extension.
M. B. Steketee and K. W. Tosney (2002)
J. Neurosci. 22, 8071-8083
   Abstract »    Full Text »    PDF »
Myelin Proteolipid Protein Forms a Complex with Integrins and May Participate in Integrin Receptor Signaling in Oligodendrocytes.
T. I. Gudz, T. E. Schneider, T. A. Haas, and W. B. Macklin (2002)
J. Neurosci. 22, 7398-7407
   Abstract »    Full Text »    PDF »
Targeting Axons to Specific Fiber Tracts In Vivo by Altering Cadherin Expression.
U. Treubert-Zimmermann, D. Heyers, and C. Redies (2002)
J. Neurosci. 22, 7617-7626
   Abstract »    Full Text »    PDF »
Regulation of Structural Plasticity by Different Channel Types in Rod and Cone Photoreceptors.
N. Zhang and E. Townes-Anderson (2002)
J. Neurosci. 22, 7065-7079
   Abstract »    Full Text »    PDF »
Filopodia and actin arcs guide the assembly and transport of two populations of microtubules with unique dynamic parameters in neuronal growth cones.
A. W. Schaefer, N. Kabir, and P. Forscher (2002)
J. Cell Biol. 158, 139-152
   Abstract »    Full Text »    PDF »
Role of Rho family GTPases in epithelial morphogenesis.
L. Van Aelst and M. Symons (2002)
Genes & Dev. 16, 1032-1054
   Full Text »    PDF »
Rapid Neuromodulatory Actions of Integrin Ligands.
W. C. Wildering, P. M. Hermann, and A. G. M. Bulloch (2002)
J. Neurosci. 22, 2419-2426
   Abstract »    Full Text »    PDF »
The C Domain of Netrin UNC-6 Silences Calcium/Calmodulin-Dependent Protein Kinase- and Diacylglycerol-Dependent Axon Branching in Caenorhabditis elegans.
Q. Wang and W. G. Wadsworth (2002)
J. Neurosci. 22, 2274-2282
   Abstract »    Full Text »    PDF »
Interaction between Metabotropic and NMDA Subtypes of Glutamate Receptors in Sprout Suppression at Young Synapses.
F. Miskevich, W. Lu, S.-Y. Lin, and M. Constantine-Paton (2002)
J. Neurosci. 22, 226-238
   Abstract »    Full Text »    PDF »
The organisation and functions of local Ca2+ signals.
M. D. Bootman, P. Lipp, and M. J. Berridge (2001)
J. Cell Sci. 114, 2213-2222
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882